An exploration into the role of the endocannabinoid system in endometrial receptivity

An Exploration into the Role of the Endocannabinoid System in Endometrial Receptivity Thesis submitted for the degree of Doctor of Philosophy at the University of Leicester by Sarah Emily Melford MBChB Reproductive Sciences Section Department of Cancer Studies and Molecular Medicine University of Leicester 2016 An Exploration into the Role of the Endocannabinoid System in Endometrial Receptivity Sarah Emily Melford, MBChB ABSTRACT While it is clear that the control of implantation is multifactorial, one emerging component that appears to be important in the success or failure of embryo implantation is the endocannabinoid system The primary ligand of the endocannabinoid system (ECS) is anandamide (AEA) which is synthesised by a N-acylphosphatidylethanolamine-specific phospholipase D (NAPEPLD) and degraded by fatty acid amide hydrolase (FAAH) A careful balance in the activities of NAPE-PLD and FAAH is required to ensure the appropriate levels of AEA are available during implantation The purpose of this thesis was to explore further the role of the ECS, specifically its role in uterine receptivity using both in-vivo and in-vitro models In-vivo models were used to study the expression of the ECS by measuring plasma concentrations of AEA, along with OEA and PEA (two other ligands of the ECS) A statistically significant change in plasma PEA concentrations was noted when comparing urine pregnancy test results No significant differences in either AEA or OEA plasma concentrations were demonstrated In-vitro models were used to investigate the interactions between galectin 3, integrin β3 and the ECS The results show that while galectin did not have any effect on the ECS, up-regulation of the expression of integrin β3 in receptive endometrial cells both increased the expression of FAAH and decreased the expression on NAPE-PLD in a dosedependent manner However, no effect was demonstrated in non-receptive endometrial cells, suggesting that integrin β3 expression, in collaboration with the ECS, plays an important role in endometrial receptivity Overall, this work gives us further insight into the immensely complex processes involved in ensuring the endometrium is receptive to an embryo Most importantly, it has suggested a link between the expression of integrin β3 and the enzymes of the ECS that is absent in the non-receptive endometrium i ACKNOWLEDGEMENTS It goes without saying that this thesis would not have been possible without the support of my supervisors, Prof Justin Konje, Dr Anthony Taylor, Miss Neelam Potdar and Dr Jonathan Willets They have continued to inspire and challenge me throughout my work, and their advice and encouragement has helped me achieve my goals I am indebted to Dr Taylor, who continued to support me after leaving his post at the University, and who I now consider to be a friend as well as a teacher Numerous members of the Cancer Studies Department rallied around when my laboratory closed, and so, a special note of thanks must be given to Dr John McDonald and Dr Raj Singh for taking an extra student under their wings I also thank all the women that were involved in my study, and the staff at the Leicester Fertility Centre for making me feel a welcomed addition to their Department Finally, I thank my family for all their support From an early age my parents have encouraged me to follow my ambitions, and have always been there to provide the necessary support to make those ambitions a reality However, the biggest ‘thank you’ must be given to my husband, who has encouraged me when I’ve felt disheartened, listened patiently when I was frustrated, and provided the occasional “reality check” when I was feeling overwhelmed (as well as doing all the cooking/cleaning while I locked myself away in the study!) I thank you all ii LIST OF CONTENTS ABSTRACT I ACKNOWLEDGEMENTS II LIST OF CONTENTS III LIST OF FIGURES VI LIST OF TABLES XI LIST OF ABBREVIATIONS XII INTRODUCTION 1.1 NORMAL PROCESS OF IMPLANTATION 1.2 PLACENTATION 1.3 IMMUNE RESPONSES TO IMPLANTATION 1.3.1 Major Histocompatibility Complex 1.3.2 Cytokines 11 1.3.3 Natural Killer Cells 14 1.4 THE WINDOW OF IMPLANTATION 16 1.5 ENDOCANNABINOID SYSTEM 20 1.5.1 Cannabinoid Receptors 21 1.5.2 Synthesis 22 1.5.3 Degradation 25 1.5.4 N-acylethanolamines 28 1.5.5 Transport across plasma membranes 29 1.6 OTHER KEY COMPONENTS INVOLVED IN UTERINE RECEPTIVITY 31 1.6.1 Prostaglandins 31 1.6.2 Leukaemia Inhibitory Factor (LIF) 32 1.6.3 HOXA-10 and HOXA-11 32 1.6.4 Galectins 33 1.6.5 Integrins 34 1.7 INVOLVEMENT OF KEY COMPONENTS IN UTERINE RECEPTIVITY 36 1.7.1 Endocannabinoids 36 1.7.2 Prostaglandins 42 1.7.3 Leukaemia Inhibitory Factor 44 1.7.4 Homeobox A10 and A11 (HOXA10 and HOXA11) 44 1.7.5 Galectins 45 1.7.6 Integrins 47 1.8 INTERACTION BETWEEN THE KEY COMPONENTS 48 1.9 HYPOTHESES AND AIMS 54 THE EFFECTS OF GALECTIN ON THE ENDOCANNABINOID SYSTEM – FEASIBILITY STUDY 56 2.1 INTRODUCTION 56 2.1.1 Choice of PCR technique 57 2.1.2 Rational for using Ishikawa cells 58 2.2 METHODS 60 2.2.1 Treatment of cells 60 2.2.2 Extraction and measurement of NAEs from culture medium 60 2.2.3 Extraction and analysis of cell RNA 60 2.2.4 RNA extraction (phenol/chloroform method) 61 2.2.5 DNAse-1 treatment of RNA sample 61 2.2.6 RNA Quantity and Quality assessment 62 2.2.7 Reverse Transcription 63 2.2.8 Polymerase Chain Reaction (PCR) 63 2.3 RESULTS 66 2.3.1 Concentration of NAEs in culture medium 66 2.3.2 Relative amounts of the key components of the ECS 72 2.4 DISCUSSION 80 iii THE EFFECTS OF GALECTIN ON THE ENDOCANNABINOID SYSTEM – FULL STUDY 82 3.1 METHODS 83 3.1.1 Cell culture 83 3.1.2 Extraction and analysis of cellular RNA 83 3.1.3 RNA Quantity and Quality assessment 83 3.1.4 DNAse treatment of RNA sample 83 3.1.5 Reverse Transcription (RT) with Multiscribe kit 84 3.1.6 Polymerase Chain Reaction 85 3.2 RESULTS 86 3.2.1 Effect of Galectin on Ishikawa cells 86 3.2.2 Correlation between ECS enzymes and NAE concentration 96 3.3 DISCUSSION 100 THE EFFECTS OF GALECTIN AND INTEGRIN Β3 ON THE ENDOCANNABINOID SYSTEM 102 4.1 INTRODUCTION 102 4.1.1 Investigating the effects of galectin (without integrin β3) 103 4.1.2 Investigating the effects of integrin β3 (without galectin 3) 104 4.2 METHODS 105 4.3 RESULTS 106 4.3.1 Effects on NAE concentration 106 4.3.2 Effects of galectin (without integrin β3) 106 4.3.3 Effects of integrin β3 (without gal-3) 112 4.4 DISCUSSION 116 THE EFFECTS OF INTEGRIN Β3 ON THE ENDOCANNABINOID SYSTEM EXPRESSION WHEN CONSIDERING ENDOMETRIAL RECEPTIVITY 120 5.1 INTRODUCTION 120 5.1.1 Choice of cell line 120 5.2 METHODS 121 5.3 RESULTS 122 5.3.1 Cell Growth 122 5.3.2 Effects of SNAP on enzyme production 124 5.4 DISCUSSION 128 ENDOCANNABINOID SYSTEM ENZYME EXPRESSION AND ENDOMETRIAL RECEPTIVITY 129 6.1 RESULTS 129 6.1.1 Relative amounts of FAAH mRNA produced by Ishikawa cells under different conditions129 6.1.2 Relative amounts of NAPE-PLD mRNA produced by Ishikawa cells in different conditions 131 6.1.3 Comparison of relative amounts of ECS enzymes’ mRNA by Ishikawa and HEC-1A cells 133 6.1.4 Comparison of the ratio ECS enzymes in Ishikawa and HEC-1A cells 135 6.1.5 Expression of the ECS enzymes in untreated Ishikawa and HEC-1A cells 137 6.2 DISCUSSION 139 IMPLANT STUDY 141 7.1 INTRODUCTION 141 7.2 MATERIALS AND METHOD 143 7.2.1 Subjects 143 7.2.2 Recruitment, randomisation and timing of blood sample collection 143 7.2.3 Initial study design 143 7.2.4 Problems with initial study design 154 7.2.5 Modified study design 156 7.3 RESULTS 157 7.3.1 Anandamide level and overall outcome of IVF/ICSI treatment 157 7.3.2 Anandamide and urinary pregnancy test result 160 7.3.3 Anandamide and pregnancy outcome in patients with a “positive” pregnancy test 162 7.4 DISCUSSION 164 iv EXPRESSION OF NAES DURING FERTILITY TREATMENT 166 8.1 PILOT STUDY 166 8.1.1 Materials and Method 167 8.1.2 Results 168 8.1.3 Discussion about the pilot study 174 8.2 FULL STUDY 175 8.2.1 Materials and Method 175 8.2.2 Results 176 8.3 DISCUSSION 192 REFECTION ON THE PROJECT 194 9.1 9.2 10 HOW DOES THESE STUDIES INFLUENCE OUR UNDERSTANDING OF ENDOMETRIAL RECEPTIVITY? 194 THINGS THAT DID NOT GO TO PLAN 195 DISCUSSION 199 10.1 PRINCIPLE FINDINGS 199 10.2 STRENGTHS AND WEAKNESSES OF THE STUDIES 199 10.3 STRENGTHS AND WEAKNESSES IN RELATION TO OTHER STUDIES 201 10.4 MEANING OF THE STUDY 203 10.5 UNANSWERED QUESTIONS AND FUTURE RESEARCH 204 10.5.1 Can plasma concentrations of OEA on the day of embryo transfer be used to predict IVF/ICIS outcome? 205 10.5.2 With a working UPLC-MS/MS (that reliably detects AEA), can the studies of El-Talatini et al be reproduced? 205 10.5.3 Does an increased expression of integrin β3 just affect the amount of NAPE-PLD and FAAH mRNA, or does it also affect enzyme expression? Furthermore, does this translate to enzyme activity? 205 10.5.4 Is it an increased expression of integrin β3 or an increased availability of nitric oxide, or both, that affects the expression of NAPE-PLD and FAAH in receptive endometrial cells? 206 10.5.5 Does the expression of integrin β3 vary between the implantation zone and interimplantation zone? 206 11 APPENDICES 207 11.1 APPENDIX - COMPARING THE EXPRESSION OF THE ENDOCANNABINOID SYSTEM AT THE IMPLANTATION ZONE AND INTER-IMPLANTATION ZONE 207 11.1.1 Protocol 207 11.1.2 Patient Information Leaflet 209 11.2 APPENDIX - COMPARING THE CONCENTRATION OF NAES IN PLASMA AND ENDOMETRIAL SAMPLES 214 11.2.1 Protocol 214 11.2.2 Patient Information Leaflet 217 11.3 APPENDIX – PUBLICATIONS AND PRESENTATIONS ARISING FROM MY THESIS 221 11.3.1 Publications 221 11.3.2 Formal presentations 221 11.3.3 Poster presentations 221 12 REFERENCES 224 v LIST OF FIGURES Figure 1-1 Different forms of placentation Figure 1-2 Proposed pathways for the synthesis of NAEs, with NAPE-PLD thought to be the main route 24 Figure 1-3 A schematic representation of the degradation of NAEs 27 Figure 1-3 A schematic representation of the degradation of NAEs 27 Figure 1-4 The interaction between the key components involved in implantation 50 Figure 1-5 The interaction of progesterone and other key components involved in endometrial receptivity 51 Figure 1-6 The role of anandamide and the other key components involved in endometrial receptivity 52 Figure 2-1 The effect of galectin on anandamide (AEA) concentrations secreted into the culture medium 67 Figure 2-2 The effect of galectin on oleoylethanolamide (OEA) concentrations secreted into the culture medium 69 Figure 2-3 The effect of galectin on palmitoylethanolamide (PEA) concentrations secreted into the culture medium 71 Figure 2-4 The effect of galectin on relative amounts of the enzyme Nacylphosphatidylethanolamine-phospholipase D (NAPE-PLD) mRNA 73 Figure 2-5 The effect of galectin relative amounts of the enzyme Fatty Acid Amide Hydrolase (FAAH) mRNA 75 Figure 2-6 The effect of galectin on the relative amounts of Cannabinoid Receptor (CB1) mRNA 77 vi Figure 2-7 The effect of galectin on the relative amounts of Cannabinoid Receptor (CB2) mRNA 79 Figure 3-1 The effect of galectin on anandamide (AEA) concentrations secreted into the culture medium 87 Figure 3-2 The effect of galectin on oleoylethanolamide (OEA) concentrations secreted into the culture medium 89 Figure 3-3 The effect of galectin on palmitoylethanolamide (PEA) concentrations secreted into the culture medium 91 Figure 3-4 The effect of galectin on relative amounts of N- acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) mRNA 93 Figure 3-5 The effect of galectin on relative amounts of Fatty Acid Amide Hydrolase (FAAH) mRNA 95 Figure 3-6 The effect of the amount of Fatty Acid Amide Hydrolase (FAAH) mRNA levels on the concentration of various NAEs 97 Figure 3-7 The effect of the amount of N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) mRNA on the concentration of various NAEs 99 Figure 4-1 The chemical structure of cilengitide, a cyclic RGD pentapeptide 103 Figure 4-2 Morphology and growth of Ishikawa cells (x100 Magnification) cultured with the following components added to the culture medium 107 Figure 4-3 The effect of galectin (without involvement of integrin β3) on relative amounts of N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) mRNA 109 Figure 4-4 The effect of galectin (without the involvement of integrin β3) on relative amounts of Fatty Acid Amide Hydrolase (FAAH) mRNA 111 vii Figure 4-5 The effect of integrin β3 (without involvement of gal-3) on the relative amounts of N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) mRNA 113 Figure 4-6 The effect of integrin β3 (without the involvement of gal-3) on relative amounts of Fatty Acid Amide Hydrolase (FAAH) mRNA 115 Figure 5-1 Morphology and growth of HEC-1A cells (x100 Magnification) cultured with the following components added to the culture medium 123 Figure 5-2 The effect of integrin β3 (without involvement of gal-3) on relative amount of N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD) mRNA 125 Figure 5-3 The effect of integrin β3 (without the involvement of gal-3) on the relative amount of Fatty Acid Amide Hydrolase (FAAH) mRNA 127 Figure 6-1 The relative amount of FAAH mRNA in Ishikawa cells treated with either SNAP, gal-3 or gal-3 + cilengitide 130 Figure 6-2 The relative amounts of NAPE-PLD mRNA in Ishikawa cells treated with either SNAP, gal-3 or gal-3 + cilengitide 132 Figure 6-3 A comparison of the relative amounts of NAPE-PLD and FAAH mRNA in Ishikawa and HEC-1A cells 134 Figure 6-4 Comparing the ratio of FAAH against NAPE-PLD in Ishikawa and HEC-1A cells at increasing concentrations of SNAP 136 Figure 6-5 Comparing the amount of NAPE-PLD and FAAH mRNA in untreated Ishikawa and HEC-1A cells 138 Figure 7-1 Schematic representation of the IMPLANT study 145 Figure 7-2 Equipment used for quantitative analysis of AEA 147 Figure 7-3 An example of the data generated from the UPLC-MS/MS 149 Figure 7-4 An example of the standard curve generated 151 viii Figure 7-5 An example of the sample and internal standard peaks generated 153 Figure 7-6 The plasma AEA concentration of women undergoing IVF or ICSI in the IMPLANT study and their overall pregnancy outcome 159 Figure 7-7 The % change in plasma AEA concentration of women undergoing IVF or ICSI in the IMPLANT study and their pregnancy test result 161 Figure 7-8 The % change in plasma AEA concentration of women undergoing IVF or ICSI in the IMPLANT study and the outcome of a positive pregnancy test 163 Figure 8-1 The plasma OEA and PEA concentrations of women undergoing IVF or ICSI in the IMPLANT study on the day of OR and their overall pregnancy outcome 169 Figure 8-2 The plasma OEA and PEA concentrations of women undergoing IVF or ICSI in the IMPLANT study on the day of 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Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates Fertility and sterility, 89(5), pp 1166-1176 ZHU, L.X., SHARMA, S., STOLINA, M., GARDNER, B., ROTH, M.D., TASHKIN, D.P and DUBINETT, S.M., 2000 Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway Journal of immunology (Baltimore, Md.: 1950), 165(1), pp 373 245 ... emerging component that appears to be important in the success or failure of embryo implantation is the endocannabinoid system The primary ligand of the endocannabinoid system (ECS) is anandamide... components of the endocannabinoid system in implantation, as identified in animal models 38 Table 1-4 Effect of the various components of the endocannabinoid system in implantation (as found in. .. 1-5 The interaction of progesterone and other key components involved in endometrial receptivity 51 Figure 1-6 The role of anandamide and the other key components involved in endometrial